Inhaled fixed-dose combination powders for the treatment of respiratory infections

ABSTRACT

Introduction

Respiratory infections are a major cause of morbidity and mortality. As an alternative to systemic drug administration, inhaled drug delivery can produce high drug concentrations in the lung tissue to overcome resistant bacteria. The development of inhaled fixed-dose combination powders (I-FDCs) is promising next step in this field, as it would enable simultaneous drug-drug or drug-adjuvant delivery at the site of infection, thereby promoting synergistic activity and improving patient compliance.

Areas covered

This review covers the clinical and pharmaceutical rationales for the development of I-FDCs for the treatment of respiratory infections, relevant technologies for particle and powder generation, and obstacles which must be addressed to achieve regulatory approval.

Expert opinion

I-FDCs have been widely successful in the treatment of asthma and chronic obstructive pulmonary disease; however, application of I-FDCs towards the treatment of respiratory infections carries additional challenges related to the high dose requirements and physicochemical characteristics of anti-infective drugs. At present, co-spray drying is an especially promising approach for the development of composite fixed-dose anti-infective particles for inhalation. Though the majority of fixed-dose research has thus far focused on the combination of multiple antibiotics, future work may shift to the additional inclusion of immunomodulatory agents or repurposed non-antibiotics.

KEYWORDS:

• COVID-19
• dry powder inhaler
• inhaled antibiotics
• mycobacterium tuberculosis
• nontuberculous mycobacterium
• particle engineering
• pulmonary drug delivery
• respiratory infection
• spray drying

Article highlights

• Inhaled fixed-dose combination powders (I-FDCs) have become a cornerstone of disease management in asthma and COPD, which provides a regulatory pathway for I-FDCs for the treatment of pulmonary infections.

• The components of the I-FDCs may be selected to overcome or prevent bacterial resistance through synergistic activity and multi-modal mechanisms of action, improve patient compliance, or promote immunomodulatory activity.

• I-FDCs carry unique challenges related to drug compatibility and their effects on physicochemical stability and pharmacokinetic activity, which must be addressed for regulatory approval.

• The majority of work thus far on I-FDCs has been performed using solution or suspension-solution co-spray dried systems. Other potentially useful technologies include physical blending, co-milling, and controlled precipitation techniques.

This box summarizes key points contained in the article.

Declaration of interest

Ashlee Brunaugh holds stock in or is employed by CloXero Therapeutics and Via Therapeutics. The terms of this arrangement have been reviewed and approved by the University of Texas at Austin in accordance with its policy on objectivity in research. Hugh D C Smyth holds stock in; serves on an advisory board for; or is a consultant for Respira Therapeutics, Nob Hill Therapeutics, and Via Therapeutics, CloXero Therapeutics. The terms of this arrangement have been reviewed and approved by the University of Texas at Austin in accordance with its policy on objectivity in research. Hugh D C Smyth has also received research funding, reimbursement, research gifts, or other support from: Amgen, ACG, Genentech, Xeris, Septum, Teva, Mylan, RCI Pharma, Elite Ambutalory, State Farm, Brickell Biotech, Meda Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers in this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Ashlee Brunaugh was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number F31HL146178. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.